Ampakines are a class of compounds observed to enhance attention span and alertness, and facilitate learning and memory in clinical trials. They take their name from the glutamatergicAMPA receptor with which they strongly interact.

These stimulants tend to increase alertness without the peripheral (body) effects or addiction/tolerance/abuse potential of "traditional" stimulants (such as amphetamine),[medical citation needed] as they lack direct dopaminergic action. Their effect on sleep structure is not fully established and may reduce quality of sleep. The ampakine CX717, when administered at doses necessary to reduce the effects of sleep deprivation, reduced subsequent stage 4 and slow-wave recovery sleep.[12] Ampakines such as ampalex and CX717 have been developed but are awaiting further research before being commercially released. They have been investigated by DARPA for potential use in increasing military effectiveness.[13]

The prototype drug in this class is modafinil, and other drugs include adrafinil, hydrafinil, and armodafinil. The primary difference between these drugs and amphetamine-like stimulants is that wakefulness-promoting agents trigger activation of neurons in the hypothalamus-based wakefulness circuits, as opposed to producing diffuse neuronal activation.[14]

Amphetamines-type stimulants are often used for their therapeutic effects. Physicians sometimes prescribe amphetamine to treat major depression, where subjects do not respond well to traditional SSRI medications,[citation needed] but evidence supporting this use is poor/mixed.[17] Notably, two recent large phase III studies of lisdexamfetamine (a prodrug to amphetamine) as an adjunct to an SSRI or SNRI in the treatment of major depressive disorder showed no further benefit relative to placebo in effectiveness.[18] Numerous studies have demonstrated the effectiveness of drugs such as Adderall (a mixture of salts of amphetamine and dextroamphetamine) in controlling symptoms associated with ADD/ADHD. Due to their availability and fast-acting effects, substituted amphetamines are prime candidates for abuse.[19]

This is the biosynthesis of catecholamines, including dopamine, as well as phenethylaminergic trace amines from the amino acid phenylalanine. Trace amines are endogenous agonists of TAAR1, the same receptor activated by amphetamine;[15] consequently, all of these trace amines are stimulants. Abbreviations: DBH, dopamine β-hydroxylase; AADC, aromatic L-amino acid decarboxylase; AAAH, aromatic amino acid hydroxylase; COMT, catechol O-methyltransferase; PNMT, phenylethanolamine N-methyltransferase

Dopamine is one of the principal neurotransmitters involved with stimulant activity in the brain, (others being norepinephrine and serotonin). Increase in its precursors may result in increased dopamine biosynthesis, especially in malnourished individuals. However levels of the enzyme tyrosine hydroxylase ultimately limit the biosynthesis regardless of increased tyrosine.

L-Tyrosine is the precursor that is 'closest' to being dopamine among those supplements legally available without prescription in most jurisdictions. It is converted by tyrosine hydroxylase into L-Dopa. Some of this L-Dopa is converted into dopamine and norepinephrine. Because tyrosine competes with other amino acids for entry into the brain supplement makers recommend tyrosine be taken on an empty stomach. However tyrosine hydroxylase is the rate limiting factor and even large dosages recommended by most supplement companies may not produce any noticeable effect. L-Phenylalanine is 'one step back' from L-Tyrosine—it must be converted into tyrosine before the tyrosine can be converted into L-Dopa, which in turn becomes dopamine. Dopamine is also the direct precursor of norepinephrine.

The first pharmaceutical amphetamine was Benzedrine, a brand of inhalers used to treat a variety of conditions.[24][27] Because the dextro isomer has greater stimulant properties, Benzedrine was gradually discontinued in favor of formulations containing all or mostly dextroamphetamine. Presently, it is typically prescribed as Adderall, dextroamphetamine (e.g., Dexedrine), or the inactive prodruglisdexamfetamine (e.g., Vyvanse).[24][35] Amphetamine, through activation of a trace amine receptor, increases biogenic amine and excitatory neurotransmitter activity in the brain, with its most pronounced effects targeting the catecholamine neurotransmitters norepinephrine and dopamine.[15] At therapeutic doses, this causes emotional and cognitive effects such as euphoria, change in libido, increased arousal, and improved cognitive control.[29][30][36] Likewise, it induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength.[28]

In contrast, much larger doses of amphetamine are likely to impair cognitive function and induce rapid muscle breakdown.[23][29][37]Substance dependence (i.e., addiction) is a serious risk of amphetamine abuse, but only rarely arises from proper medical use.[23][38] Very high doses can result in a psychosis (e.g., delusions and paranoia), which very rarely occurs at therapeutic doses even during long-term use.[39][40] As recreational doses are generally much larger than prescribed therapeutic doses, recreational use carries a far greater risk of serious side effects.[23][37]

Caffeine is a stimulant compound belonging to the xanthine class of chemicals naturally found in coffee, tea, and (to a lesser degree) cocoa or chocolate. It is included in many soft drinks, as well as a larger amount in energy drinks. Caffeine is the world's most widely used psychoactive drug and by far the most common stimulant. In North America, 90% of adults consume caffeine daily.[47] A few jurisdictions restrict its sale and use. Caffeine is also included in some medications, usually for the purpose of enhancing the effect of the primary ingredient, or reducing one of its side-effects (especially drowsiness). Tablets containing standardized doses of caffeine are also widely available.

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy, or molly), typically comes as tablets, capsules, and in powder/crystal form. Briefly used by some psychotherapists as an adjunct to therapy, the drug became popular recreationally and the DEA listed MDMA as a Schedule I controlled substance, prohibiting most medical studies and applications. MDMA is known for its entactogenic properties. The stimulant effects of MDMA include hypertension, anorexia (appetite loss), euphoria, social disinhibition, insomnia (enhanced wakefulness/inability to sleep), improved energy, increased arousal, and increased perspiration, among others.

Methylenedioxypyrovalerone (MDPV) is a psychoactive drug with stimulant properties that acts as a norepinephrine-dopamine reuptake inhibitor (NDRI).[49] It was first developed in the 1960s by a team at Boehringer Ingelheim.[50] MDPV remained an obscure stimulant until around 2004, when it was reported to be sold as a designer drug. Products labeled as bath salts containing MDPV were previously sold as recreational drugs in gas stations and convenience stores in the United States, similar to the marketing for Spice and K2 as incense.[51][52]

Incidents of psychological and physical harm have been attributed to MDPV use.[53][54]

Mephedrone is a synthetic stimulant drug of the amphetamine and cathinone classes. Slang names include drone[55] and MCAT.[56] It is reported to be manufactured in China and is chemically similar to the cathinone compounds found in the khat plant of eastern Africa. It comes in the form of tablets or a powder, which users can swallow, snort, or inject, producing similar effects to MDMA, amphetamines, and cocaine.

Mephedrone was first synthesized in 1929, but did not become widely known until it was rediscovered in 2003. By 2007, mephedrone was reported to be available for sale on the Internet; by 2008 law enforcement agencies had become aware of the compound; and, by 2010, it had been reported in most of Europe, becoming particularly prevalent in the United Kingdom. Mephedrone was first made illegal in Israel in 2008, followed by Sweden later that year. In 2010, it was made illegal in many European countries, and, in December 2010, the EU ruled it illegal. In Australia, New Zealand, and the USA, it is considered an analog of other illegal drugs and can be controlled by laws similar to the Federal Analog Act. In September 2011, the USA temporarily classified mephedrone as illegal, in effect from October 2011.

In the United States, PPA is no longer sold without a prescription due to a proposed increased risk of stroke in younger women. In a few countries in Europe, however, it is still available either by prescription or sometimes over-the-counter. In Canada, it was withdrawn from the market on 31 May 2001.[67] In India, human use of PPA and its formulations were banned on 10 February 2011.[68]

Propylhexedrine (Hexahydromethamphetamine, Obesin) is a stimulant medication, sold over-the-counter in the United States as the cold medication Benzedrex.[69] The drug has also been used as an appetite suppressant in Europe. Propylhexedrine is not an amphetamine, though it is structurally similar; it is instead a cycloalkylamine, and thus has stimulant effects that are less potent than similarly structured amphetamines, such as methamphetamine.

The abuse potential of propylhexedrine is fairly limited, due its limited routes of administration: in the United States, Benzedrex is only available as an inhalant, mixed with lavender oil and menthol. These ingredients cause unpleasant tastes, and abusers of the drug have reported unpleasant "menthol burps." Injection of the drug has been found to cause transient diplopia and brain stem dysfunction.[70][71][72]

Dimethylamylamine is a stimulant drug, once sold in over-the-counter workout supplements and study aids in the United States as in the supplement Jack 3D, but it was later discontinued. Dimethylamylamine is not an amphetamine, though it is structurally similar, and thus has stimulant effects that are less potent than similarly structured amphetamines, such as amphetamine.

Cocaine is an SNDRI. Cocaine is made from the leaves of the coca shrub, which grows in the mountain regions of South American countries such as Bolivia, Colombia, and Peru. In Europe, North America, and some parts of Asia, the most common form of cocaine is a white crystalline powder. Cocaine is a stimulant but is not normally prescribed therapeutically for its stimulant properties, although it sees clinical use as a local anesthetic, in particular in ophthalmology. Most cocaine use is recreational and its abuse potential is high (albeit higher than amphetamine), and so its sale and possession are strictly controlled in most jurisdictions. Other tropane derivative drugs related to cocaine are also known such as troparil and lometopane but have not been widely sold or used recreationally.[79]

Use of stimulants may cause the body to reduce significantly its production of natural body chemicals that fulfill similar functions. Until the body reestablishes its normal state, once the effect of the ingested stimulant has worn off the user may feel depressed, lethargic, confused, and miserable. This is referred to as a "crash", and may provoke reuse of the stimulant.

The presence of stimulants in the body may be tested by a variety of procedures. Serum and urine are the common sources of testing material although saliva is sometimes used. Commonly used tests include chromatography, immunologic assay, and mass spectrometry.[81] Patients taking ADHD-prescribed, Adderall-type amphetamine compounds are commonly surprised upon being tested as "positive" for "meth", or methamphetamine (Desoxyn—its licit, FDA-licensed, medicinal form) in forensically unsophisticated urinalysis, as methamphetamine is the active ingredient of the drug Desoxyn, and is chemically similar to the active ingredients of other ADHD medications.

^Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.
Levoamphetamine and dextroamphetamine are also known as L-amph or levamfetamine (INN) and D-amph or dexamfetamine (INN) respectively.

^The active ingredient in some OTC inhalers in the United States is listed as levmetamfetamine, the INN and USAN of levomethamphetamine.[63][64]

^Wang X, Li J, Dong G, Yue J (February 2014). "The endogenous substrates of brain CYP2D". Eur. J. Pharmacol. 724: 211–218. doi:10.1016/j.ejphar.2013.12.025. PMID24374199. The highest level of brain CYP2D activity was found in the substantia nigra (Bromek et al., 2010). The in vitro and in vivo studies have shown the contribution of the alternative CYP2D-mediated dopamine synthesis to the concentration of this neurotransmitter although the classic biosynthetic route to dopamine from tyrosine is active. CYP2D6 protein level is approximately 40% lower in the frontal cortex, cerebellum, and hippocampus in PD patients, even when controlling for CYP2D6 genotype (Mann et al., 2012). ... Tyramine levels are especially high in the basal ganglia and limbic system, which are thought to be related to individual behavior and emotion (Yu et al., 2003c). Studies have demonstrated that dopamine is formed from p-tyramine as well as m-tyramine via tyramine 3-hydroxylation or 4-hydroxylation by rat CYP2D2, 2D4, and 2D18 as well as human CYP2D6. ... Both rat CYP2D and human CYP2D6 have a higher affinity for m-tyramine compared with p-tyramine for the generation of dopamine. Rat CYP2D isoforms (2D2/2D4/2D18) are less efficient than human CYP2D6 for the generation of dopamine from p-tyramine. The Km values of the CYP2D isoforms are as follows: CYP2D6 (87–121 μm) ≈ CYP2D2 ≈ CYP2D18 > CYP2D4 (256 μm) for m-tyramine and CYP2D4 (433 μm) > CYP2D2 ≈ CYP2D6 > CYP2D18 (688 μm) for p-tyramine (Bromek et al., 2010; Thompson et al., 2000).

^ abcMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 318. ISBN978-0-07-148127-4. Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in individuals with ADHD and in normal subjects...it is now believed that dopamine and norepinephrine, but not serotonin, produce the beneficial effects of stimulants on working memory. At abused (relatively high) doses, stimulants can interfere with working memory and cognitive control, as will be discussed below. It is important to recognize, however, that stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks...through indirect stimulation of dopamine and norepinephrine receptors.

^Stolerman IP (2010). Stolerman IP, ed. Encyclopedia of Psychopharmacology. Berlin; London: Springer. p. 78. ISBN978-3-540-68698-9. Although [substituted amphetamines] are also used as recreational drugs, with important neurotoxic consequences when abused, addiction is not a high risk when therapeutic doses are used as directed.

^ abBroadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID19948186. Fig. 2. Synthetic and metabolic pathways for endogenous and exogenously administered trace amines and sympathomimetic amines...
Trace amines are metabolized in the mammalian body via monoamine oxidase (MAO; EC 1.4.3.4) (Berry, 2004) (Fig. 2)...It deaminates primary and secondary amines that are free in the neuronal cytoplasm but not those bound in storage vesicles of the sympathetic neurone...
Thus, MAO inhibitors potentiate the peripheral effects of indirectly acting sympathomimetic amines. It is not often realized, however, that this potentiation occurs irrespective of whether the amine is a substrate for MAO. An α-methyl group on the side chain, as in amphetamine and ephedrine, renders the amine immune to deamination so that they are not metabolized in the gut. Similarly, β-PEA would not be deaminated in the gut as it is a selective substrate for MAO-B which is not found in the gut...
Brain levels of endogenous trace amines are several hundred-fold below those for the classical neurotransmitters noradrenaline, dopamine and serotonin but their rates of synthesis are equivalent to those of noradrenaline and dopamine and they have a very rapid turnover rate (Berry, 2004). Endogenous extracellular tissue levels of trace amines measured in the brain are in the low nanomolar range. These low concentrations arise because of their very short half-life,...